The present invention relates to a process for synthesizing carbapenem intermediates and compounds produced. Generally hydroxymethylcarbapenems are substituted at the 2-position through a CH2 link with various sidechains to prepare anti-methicillin resistant Staphylococcus aureus (MRSA) compounds. The intermediate compounds are included as well. Examples of carbapenems which are substituted with a naphthosultam-containing side chain at the 2-position are found in Schmitt, S. M. et al., J. Antibiotics 41(6): 780-787 (1988) and U.S. Pat. No. 5,756,725, issued May 26, 1998, the teachings of which are hereby incorporated by reference. European applications 0330108, 0102239, 0212404, 0695753 and 0476649 also disclose methods for synthesizing various antibiotic derivatives.
Many of the carbapenems are useful against gram positive microorganisms, especially methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant Staphylococcus epidermidis (MRSE), and methicillin resistant coagulase negative Staphylococci (MRCNS). These antibacterials thus comprise an important contribution to therapy for treating infections caused by these difficult to control pathogens. There is an increasing need for agents effective against such pathogens (MRSA/MRCNS) which are at the same time relatively free from undesirable side effects.
In one aspect of the invention, a process of synthesizing a carbapenem compound of formula 6: 
is disclosed wherein:
R represents H or methyl,
P* represents H, negative charge, or a carboxy protecting group;
P represents hydrogen, hydroxyl, or hydroxy-protecting group; and
each R1 is independently selected from: xe2x80x94R*; xe2x80x94Q; hydrogen; halo; xe2x80x94CN; xe2x80x94NO2; xe2x80x94NRaRb; xe2x80x94ORc; xe2x80x94SRc; xe2x80x94C(O)NRaRb; xe2x80x94C(O)ORh; xe2x80x94S(O)Rc; xe2x80x94SO2Rc; xe2x80x94SO2NRaRb; xe2x80x94NRaSO2Rb; xe2x80x94C(O)Ra; xe2x80x94OC(O)Ra; xe2x80x94OC(O)NRaRb; xe2x80x94NRaC(O)NRbRc; xe2x80x94NRaCO2Rh; xe2x80x94OCO2Rh; xe2x80x94NRaC(O)Rb; xe2x80x94C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Rd groups; and xe2x80x94C3-7 cycloalkyl, unsubstituted or substituted with one to four Rd groups;
each Ra, Rb and Rc independently represents hydrogen, xe2x80x94R*, xe2x80x94C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Rd groups, or xe2x80x94C3-7 cycloalkyl, unsubstituted or substituted with one to four Rd groups;
or Ra and Rb taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NRc, with Rc as defined above, or xe2x80x94C(O)xe2x80x94, said ring being unsubstituted or substituted with one to four Ri groups;
or Rb and Rc taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of O, S, NRa, with Ra as defined above, or xe2x80x94C(O)xe2x80x94, said ring being unsubstituted or substituted with one to four Ri groups;
each Rd independently represents halo; xe2x80x94CN; xe2x80x94NO2; xe2x80x94NReRf; xe2x80x94ORg; xe2x80x94SRg; xe2x80x94CONReRf; xe2x80x94COORg; xe2x80x94SORg; xe2x80x94SO2Rg; xe2x80x94SO2NReRf; xe2x80x94NReSO2Rf; xe2x80x94CORe; xe2x80x94NReCORf; xe2x80x94OCORe; xe2x80x94OCONReRf; xe2x80x94NReONRfRg; xe2x80x94NReCO2Rh; xe2x80x94OCO2Rh; xe2x80x94C(NRe)NRfRg; xe2x80x94NReC(NH)NRfRg; xe2x80x94NReC(NRf)Rg; xe2x80x94R* orxe2x80x94Q;
Re, Rf and Rg represent hydrogen; xe2x80x94R*; xe2x80x94C1-6 straight- or branched-chain alkyl unsubstituted or substituted with one to four Ri groups;
or Re and Rf taken together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one to three of O, S, xe2x80x94C(O)xe2x80x94or NRg with Rg as defined above, said ring being unsubstituted or substituted with one to four Ri groups;
each Ri independently represents halo; xe2x80x94CN; xe2x80x94NO2; phenyl; xe2x80x94NHSO2Rh; xe2x80x94ORh, xe2x80x94SRh; xe2x80x94N(Rh)2; xe2x80x94N+(Rh)3; xe2x80x94C(O)N(Rh)2; xe2x80x94SO2N(Rh)2; heteroaryl; heteroarylium; xe2x80x94CO2Rh; xe2x80x94C(O)Rh; xe2x80x94OCORh; xe2x80x94NHCORh; guanidinyl; carbamimidoyl or ureido;
each Rh independently represents hydrogen, a xe2x80x94C1-6 straight or branched-chain alkyl group, a xe2x80x94C3-6 cycloalkyl group or phenyl, or when two Rh groups are present, said Rh groups may be taken in combination and represent a 4-6 membered saturated ring, optionally interrupted by one or two of O, S, SO2, xe2x80x94C(O)xe2x80x94, NH and NCH3;
Q is selected from the group consisting of: 
xe2x80x83wherein:
a and b are 1, 2 or 3;
Lxe2x88x92 is a pharmaceutically acceptable counterion;
xcex1 represents O, S or NRs;
xcex2, xcex4, xcex, xcexc and "sgr" represent CRt, N or N+Rs, provided that no more than one of xcex2, xcex4, xcex, xcexc and "sgr" is N+Rs;
R* is selected from the group consisting of: 
xe2x80x83wherein:
d represents O, S or NRk;
e, g, x, y and z represent CRm, N or N+Rk, provided that no more than one of e, g, x, y and z in any given structure represents N+Rk;
Rk represents hydrogen; xe2x80x94C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; or xe2x80x94(CH2)nQ where n=1, 2 or 3 and Q is as previously defined;
each Rm independently represents a member selected from the group consisting of: hydrogen; halo; xe2x80x94CN; xe2x80x94NO2; xe2x80x94NRnRo; xe2x80x94ORn; xe2x80x94SRn; xe2x80x94CONRnRo; xe2x80x94COORh; xe2x80x94SORn; xe2x80x94SO2Rn; xe2x80x94SO2NRnRo; xe2x80x94NRnSO2Ro; xe2x80x94CORn; xe2x80x94NRnCORo; xe2x80x94OCORn; xe2x80x94OCONRnRo; xe2x80x94NRnCO2Rh; xe2x80x94NRnCONRoRh; xe2x80x94OCO2Rh; xe2x80x94CNRnNRoRh; xe2x80x94NRnCNHNRoRh; xe2x80x94NRnC(NRo)Rh; xe2x80x94C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; xe2x80x94C3-7 cycloalkyl, unsubstituted or substituted with one to four Ri groups; and xe2x80x94(CH2)nQ where n and Q are as defined above;
Rn and Ro represent hydrogen, phenyl; xe2x80x94C1-6 straight- or branched-chain alkyl unsubstituted or substituted with one to four Ri groups;
each Rs independently represents hydrogen; phenyl or xe2x80x94C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups;
each Rt independently represents hydrogen; halo; phenyl; xe2x80x94CN; xe2x80x94NO2; xe2x80x94NRuRv; xe2x80x94ORu; xe2x80x94SRu; xe2x80x94CONRuRv; xe2x80x94COORh; xe2x80x94SORu; xe2x80x94SO2Ru; xe2x80x94SO2NRuRv; xe2x80x94NRuSO2Rv; xe2x80x94CORu; xe2x80x94NRuCORv; xe2x80x94OCORu; xe2x80x94OCONRuRv; xe2x80x94NRuCO2Rv; xe2x80x94NRuCONRvRw; xe2x80x94OCO2Rv; xe2x80x94C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups;
Ru and Rv represent hydrogen or xe2x80x94C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups;
or Ru and Rv together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by one or more of O, S, NRw or xe2x80x94C(O)xe2x80x94, said ring being unsubstituted or substituted with one to four Ri groups;
each Rw independently represents hydrogen; xe2x80x94C1-6 straight- or branched-chain alkyl, unsubstituted or substituted with one to four Ri groups; C3-6 cycloalkyl optionally substituted with one to four Ri groups; phenyl optionally substituted with one to four Ri groups, or heteroaryl optionally substituted with 1-4 Ri groups;
or Rh and Rw taken together with any intervening atoms represent a 5-6 membered saturated ring, optionally interrupted by one or two of O, S, SO2, NH or NCH3;
Rx represents hydrogen or a C1-8 straight- or branched-chain alkyl, optionally interrupted by one or two of O, S, SO, SO2, NRw, N+RhRw, or xe2x80x94C(O)xe2x80x94, said chain being unsubstituted or substituted with one to four of halo, CN, NO2, ORw, SRw, SORw, SO2Rw, NRhRw, N+(Rh)2Rw, xe2x80x94C(O)xe2x80x94Rw, C(O)NRhRw, SO2NRhRw, CO2Rw, OC(O)Rw, OC(O)NRhRw, NRhC(O)Rw, NRhC(O)NRhRw, or a phenyl or heteroaryl group which is in turn optionally substituted with from one to four Ri groups or with one to two C1-3 straight- or branched-chain alkyl groups, said alkyl groups being unsubstituted or substituted with one to four Ri groups;
Ry and Rz represent hydrogen; phenyl; xe2x80x94C1-6 straight or branched chain alkyl, unsubstituted or substituted with one to four Ri groups, and optionally interrupted by O, S, NRw, N+RhRw or xe2x80x94C(O)xe2x80x94;
or Rx and Ry together with any intervening atoms represent a 4-6 membered saturated ring optionally interrupted by O, S, SO2, NRw, N+RhRwor xe2x80x94C(O)xe2x80x94, unsubstituted or substituted with 1-4 Ri groups,
and when Rx and Ry together represent a 4-6 membered ring as defined above, Rz is as defined above or Rz represents an additional saturated 4-6 membered ring fused to the ring represented by Rx and Ry taken together, optionally interrupted by O, S, NRw or xe2x80x94C(O)xe2x80x94, said rings being unsubstituted or substituted with one to four Ri groups;
comprising reacting a carbapenem of formula 4xe2x80x2: 
with a compound of formula 7: 
wherein R, R1, P and P* are as previously defined and R2 represents C(O)ORxe2x80x2, C(O)Rxe2x80x2 or P(O)(ORxe2x80x3)2, wherein Rxe2x80x2 and Rxe2x80x3 independently represent C1-6 alkyl, aryl or benzyl, in the presence of a catalyst to produce a compound of formula 6.
In another aspect of the invention there is disclosed a compound of formula 4 
or a pharmaceutically acceptable salt thereof;
wherein P, P*, and R are described above and R2 is C(O)Rxe2x80x2 or C(O)ORxe2x80x2, wherein Rxe2x80x2 represents C1-6 alkyl, aryl or benzyl.
The invention is described herein in detail using the terms defined below unless otherwise specified.
The term xe2x80x9calkylxe2x80x9d refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 10 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl cyclopentyl and cyclohexyl. When substituted, alkyl groups may be substituted with up to four substituent groups, selected from Rd and Ri , as defined, at any available point of attachment. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with xe2x80x9cbranched alkyl groupxe2x80x9d.
Cycloalkyl is a specie of alkyl containing from 3 to 15 carbon atoms, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings which are fused.
The term xe2x80x9calkenylxe2x80x9d refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.
The term xe2x80x9calkynylxe2x80x9d refers to a hydrocarbon radical straight or branched, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond. Preferred alkynyl groups include ethynyl, propynyl and butynyl.
Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and the like, as well as rings which are fused, e.g., naphthyl, phenanthrenyl and the like. An aryl group thus contains at least one ring having at least 6 atoms, with up to five such rings being present, containing up to 22 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms or suitable heteroatoms. The preferred aryl groups are phenyl, naphthyl and phenanthrenyl. Aryl groups may likewise be substituted as defined. Preferred substituted aryls include phenyl and naphthyl.
The term xe2x80x9cheteroarylxe2x80x9d refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted as described herein. Examples of this type are pyrrole, pyridine, oxazole, thiazole and oxazine. Additional nitrogen atoms may be present together with the first nitrogen and oxygen or sulfur, giving, e.g., thiadiazole. Examples include the following: 
Heteroaryliulm refers to heteroaryl groups bearing a quaternary nitrogen atom and thus a positive charge. Examples include the following: 
When a charge is shown on a particular nitrogen atom in a ring which contains one or more additional nitrogen atoms, it is understood that the charge may reside on a different nitrogen atom in the ring by virtue of charge resonance that occurs. 
The term xe2x80x9cheterocycloalkylxe2x80x9d refers to a cycloalkyl group (nonaromatic) in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S or N, and in which up to three additional carbon atoms may be replaced by hetero atoms.
The terms xe2x80x9cquaternary nitrogenxe2x80x9d and xe2x80x9cpositive chargexe2x80x9d refer to tetravalent, positively charged nitrogen atoms including, e.g., the positively charged nitrogen in a tetraalkylammonium group (e. g. tetramethylammonium), heteroarylium, (e.g., N-methyl-pyridinium), basic nitrogens which are protonated at physiological pH, and the like. Cationic groups thus encompass positively charged nitrogen-containing groups, as well as basic nitrogens which are protonated at physiologic pH.
The term xe2x80x9cheteroatomxe2x80x9d means O, S or N, selected on an independent basis.
Halogen and xe2x80x9chaloxe2x80x9d refer to bromine, chlorine, fluorine and iodine.
Alkoxy refers to C1-C4 alkyl-Oxe2x80x94, with the alkyl group optionally substituted as described herein.
When a group is termed xe2x80x9cprotectedxe2x80x9d, such as by P, P* and the like, this means that the group is in modified form to preclude undesired side reactions at the protected site. Suitable protecting groups for the compounds of the present invention will be recognized from the present application taking into account the level of skill in the art, and with reference to standard textbooks, such as Greene, T. W. et al. Protective Groups in Organic Synthesis Wiley, New York (1991). Examples of suitable protecting groups are contained throughout the specification.
In some of the compounds of the present invention, P and P* represent hydroxyl and carboxyl protecting groups, respectively. These groups are generally removable, i.e., they can be removed, if desired, by procedures which will not cause cleavage or other disruption of the remaining portions of the molecule. Such procedures include chemical and enzymatic hydrolysis, treatment with chemical reducing or oxidizing agents under mild conditions, treatment with a transition metal catalyst and a nucleophile and catalytic hydrogenation.
Examples of carboxyl protecting groups P* include allyl, benzhydryl, 2-naphthylmethyl, benzyl, silyl groups such as t-butyldimethylsilyl (TBDMS), trimethylsilyl, (TMS), triethylsilyl (TES), and trimethylsilylethyl, phenacyl, p-methoxybenzyl, o-nitrobenzyl, p-methoxyphenyl, p-nitrobenzyl, 4-pyridylmethyl, 2,2,2-trichloroethyl, and t-butyl.
Examples of suitable hydroxy protecting groups P include TMS, TES, TBDMS, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl and the like.
With respect to xe2x80x94CO2P*, which is attached to the carbapenem nucleus at position 3, this can represent a carboxylic acid group (P* represents H), a carboxylate anion (P* represents a negative charge), a pharmaceutically acceptable ester (P* represents an ester forming group) or a carboxylic acid protected by a protecting group (P* represents a carboxyl protecting group). The pharmaceutically acceptable salts referred to above may take the form xe2x80x94COO P*, where P* is a negative charge, which is balanced by a counterion, e.g., an alkali metal cation such as sodium or potassium. Other pharmaceutically acceptable counterions may be calcium, magnesium, zinc, ammonium, or alkylammonium cations such as tetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium, meglumine, triethanolhydroammonium, etc.
The pharmaceutically acceptable salts referred to above also include phosphate, sulfate and acid addition salts. Thus, the Formula 4 compounds can be used in the form of salts derived from inorganic or organic acids. Included among such salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, sulfate, tosylate and undecanoate.
The pharmaceutically acceptable esters are such as would be readily apparent to a medicinal chemist, and include, for example, those described in detail in U.S. Pat. No. 4,309,438. Included within such pharmaceutically acceptable esters are those which are hydrolyzed under physiological conditions, such as pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, and others described in detail in U.S. Pat. No. 4,479,947. These are also referred to as xe2x80x9cbiolabile estersxe2x80x9d.
A base can optionally be added to the process. Suitable bases include trialkylamines such as triethylamine, trimethylamine, ethyldimethylamine, tri-n-propylamine and the like, 1,8-diazabicyclo[5.4.0.]undec-7-ene (DBU), pyridine, lutidine, collidine, 4-dimethylaminomethyl-pyridine, inorganic carbonates and bicarbonates such as sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium carbonate, and the like and tartrates such as potassium sodium tartrate, potassium tartrate, potassium bitartrate, sodium tartrate, sodium bitartrate and the like. Preferable bases are pyridine, potassium sodium tartrate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, or potassium carbonate.
Suitable catalyst are those which contain a palladium (Pd) source, preferably those which contain a palladium and a phosphine ligand source or a phosphite ligand source. Examples of a palladium sources Pd(OAc)2, Pd(PPh3)4PdCl2, PdCl2(PPh3)2, PdCl2(CH3CN)2 and Pd2DBA3, and the like, wherein DBA is dibenzylidene acetone. Examples of ligands are triphenylarsine, trifurylphosphine, trialkylphosphites (P(OR+)3; wherein R+ is C1-10 alkyl), such as triethylphosphite, tributylphosphite, trimethylphosphite, triisopropylphosphite and the like, triarylphosphite such as triphenylphosphite (referred to as PPh3 or TPP) and the like, DPPE, DPPP, preferably triarylphosphite or trialkylphosphites and most preferably C1-4 phosphite or PPh3. Examples of catalysts containing ligands are Pd(OAc)2/TPP, Pd2(DBA)3/TPP and the like.
The reaction is generally carried out using a solvent such as toluene, C1-6 alcohols such as isopropyl alcohol, methanol, ethanol, hexanol, butanol, and the like, acetronitrile, tetrahydrofuran (THF), ether, ester such as ethyl acetate, isopropylacetate and the like, benzene, dimethylformamide, N-methylpyrolidinone, dimethylsulfoxide and the like or a combination of the above with water.
In particular, processes of interest are those described above wherein P represents a member selected from the group consisting of TMS, TES, TBDMS, trimethylsilylethyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, t-butyloxycarbonyl, 2,2,2-trichlorethyl and 2,2,2-trichloroethyloxycarbonyl.
Other processes that are of particular interest are those described above wherein P* represents a member selected from the group consisting of: allyl, benzhydryl, 2-naphthylmethyl, benzyl, silyl groups such as t-butyldimethylsilyl (TBDMS), trimethylsilyl, (TMS), triethylsilyl (TES), trimethylsilylethyl, phenacyl, p-methoxybenzyl, o-nitrobenzyl, p-methoxyphenyl, p-nitrobenzyl (PNB), 4-pyridylmethyl, 2,2,2-trichlorethyl and t-butyl.
Still other processes that are of particular interest are those described above wherein R represents methyl.
Still other processes that are of particular interest are those described above wherein at least one R1 represents a positive charged.
Still other processes that are of particular interest are those described above wherein R2 represents C(O)ORxe2x80x2 or P(O)(ORxe2x80x3)2 and most preferably C(O)ORxe2x80x2.
Still other processes that are of particular interest are those described above wherein R, P and P* are described above and one R1 group represents a xe2x80x94C1-6 straight or branched chain alkyl group, substituted with one to four Rd groups, wherein one Rd group represents xe2x80x94R* or Q;
In another embodiment of the invention a process for making a compound of formula 6: 
is disclosed wherein R, R1, P and P* are described above;
comprising
Step 1.
reacting a carbapenem of formula 3: 
with an alkylhaloformate in the presence of a base to produce a compound of formula 4xe2x80x2: 
Step 2.
reacting 4xe2x80x2 with a compound of formula 7: 
wherein R, R1, P and P* are as previously defined and R2 represents C(O)ORxe2x80x2, C(O)Rxe2x80x2 or P(O)(ORxe2x80x3)2, wherein Rxe2x80x2 and Rxe2x80x3 independently represent C1-6 alkyl, benzyl or aryl, in the presence of a catalyst to produce a compound of formula 6. Examples of alkylhaloformates are isobutylchloroformate, ethylchloroformate, methylchoroformate, propylchloroformate and the like, preferably isobutylchloroformate or ethylchloroformate. In another aspect of this invention a base, such as those previously mentioned, is optionally added to Step 2.
The process of the present invention is illustrated by the following generic scheme: 
With reference to Flow Sheet A, the naphthosultam side chain group (SCG) 7 used in the synthesis of the compounds of the present invention have, in some cases, been described in the chemical literature. In other cases, precursor compounds which may be readily converted to the requisite naphthosultam have been described in the literature. In cases where the requisite naphthosultam is not known in the literature it is neceessary to synthesize the naphthosultam by a newly developed synthesis. One skilled in the art can adapt a previously published synthesis of an analogous naphthosultam to prepare the requisite compound in a straightforward manner without undue experimentation. Examples of naphthosultam synthesis are described herein (see below).
The naphthosultam side chain group (SCG) is initially reacted with a suitably protected carbapen-2-em-3-carboxylate 1 having an activated hydroxymethyl group at the 2-position.
The carbapenem nucleus 1 having a xe2x80x94CH2OH substituent at position 2 can be obtained in accordance with Schmitt, S. M. et al., J. Antibiotics 41(6): 780-787 (1988). The compounds disclosed in U.S. Pat. No. 5,756,725, issued May 26, 1998 can also be prepared in accordance with the invention herein. The carboxylic acid group at C-3 of the carbapenem is generally protected as a carboxyl protecting group such as p-nitrobenzyl (PNB), allyl, p-methoxybenzyl, trichloroethyl, 2-trimethylsilylethyl, and the like. Furthermore, the hydroxyl group of the 6-(hydroxyethyl) side-chain is optionally protected with a hydroxyl protecting group such as trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl, allyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-trichloroethoxycarbonyl and the like.
The carbapenem 4xe2x80x2 can be made in accordance with techniques such as those which are disclosed in U.S. Pat. Nos. 5,034,384, 4,994,568 and 5,478,820, herein incorporated by reference. For example, carbapenem 4xe2x80x2 can be obtained by reacting carbapenem 1, wherein P is TES and P* is PNB, with a weak base such as pyridine in the presence of a solvent, and adding a C1-6 alkylchloroformate such as isobutylchloroformate or ethylchloroformate. Preferred carabapenem compounds of 4xe2x80x2 are those in which R2 is an allylic C1-6 carbonate, C1-6 phosphate or ester such as acetate, most preferably an allyic C1-6 carbonate.
In general, the addition of the naphthosultam side chain group 7 (SCG) to the carbapenem 4xe2x80x2 is accomplished by reacting the carbapenem 4xe2x80x2 with the naphthosultam side chain group 7 in a suitable solvent such as tetrahydrofuran (THF), ether, acetonitrile, a C1-6 alcohol such as isopropanol, dimethylformamide (DMF), benzene, dimethylsulfoxide (DMSO), and the like, preferably acetonitrile or isopropanol, in the presence of a palladium catalyst sytem, described above, at a temperature between about 0xc2x0 C. and 150xc2x0 C., preferably about 15xc2x0 C. to about 50 xc2x0 C., and most preferably about 20xc2x0 C. to about 35xc2x0 C., for about 5 to 90 minutes followed by an appropriate workup and isolation procedure familiar to those skilled in the art to yield the compounds of 6. A base, described above, can also be optionally added to the process.
The preferable palladium catalyst system is one which includes a ligand. Examples of such catalyst systems are Pd(OAc)2/TPP, Pd2(DBA)3TPP, Pd(OAc)2/triethylphosphite, Pd(OAc)2/trifurylphosphine, Pd2(DBA)3/trifurylphosphine, Pd2(DBA)3/triethylphosphite and the like, with an optimal palladium level of about 0.1 mole % to about 15 mole %, preferably about 0.5 mole % to about 2 mole % and an optimal ligand level of about 0.3 mole % to about 45 mole %, preferably about 6 to about 11 mole %.
In the case where a trialkylphosphite such as triethylphosphite, triarylphosphite such as triphenylphosphite or triarylphosphine such as trifurylphosphine ligand is employed it is preferred that the temperature range is about 20xc2x0 C. to about 35xc2x0 C., which allows for direct coupling of a charged (i.e., at least one R1 is charged) substituted naphthosultam to the carbapenem carbonate.
With reference to Flow Sheet B, the compounds of 2 can be prepared by modifying the naphthosultam side chain of 6 as desired, and then removing any protecting groups which are present to afford the desired final product as taught in U.S. Pat. No. 5,756,725, herein incorporated by reference.
To obtain the compounds disclosed in U.S. Pat. No. 5,756,725, modification of the naphthosultam side chain of compounds 6, which is generally necessary to introduce the charged substituent of 2, is best accomplished before removal of the protecting groups. For compounds which contain a hydroxyl group in the side chain, i.e. in R1, a positively charged substituent may be introduced into the side chain by first activating the hydroxyl group by converting it to a suitable leaving group such as a triflate, mesylate, tosylate, iodide, chloride, bromide, and the like, and then displacing the resulting leaving group with a compound Q*, such as N-methyl-imidazole, N-(2-hydroxyethyl)-imidazole, N-methyl-diazabicyclooctane, 1-(carbamoylmethyl)-4-aza-1-azoniabicyclo-[2.2.2.]-octane, 1-(3-hydroxyprop-1-yl)-4-aza-1-azoniabicyclo-[2.2.2.]-octane, pyridine, morpholine and the like which contains a nitrogen atom that can act as a nucleophile.
Alternatively, in some cases, the charged substituent may be incorporated in the naphthosultam side chain before addition of the naphthosultam to the carbapenem, which is preferred when a trialkylphosphite or triarylphosphite ligand is employed in the catalyst system. Alternatively, the charged substituent may be introduced after deprotection of 6. However, introduction of the charged substituent by modification of 6 before deprotection is greatly preferred.
In some cases, activation of the hydroxyl group and displacement by Q* to produce 2 may be accomplished in a single step by taking advantage of the basic character of compound Q* and using it as a base in the activation reaction.
The conversion of the hydroxyl group to a suitable leaving group is accomplished by treating the hydroxyl substituted compound in a suitable solvent such as dichloromethane, dichloroethane, toluene, tetrahydrofuran, ether, acetonitrile, benzene, and the like with an activating reagent, such as trifluoromethanesulfonic anhydride, methanesulfonic anhydride, toluenesulfonic anhydride, methanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, and the like in the presence of a suitable base such as triethylamine, tributylamine, lutidine, diisopropylethylamine, and the like at a temperature of between about xe2x80x94100xc2x0 C. and about 0xc2x0 C. for about 5 to about 120 minutes. The intermediate thus obtained contains a leaving group, which may be converted to an alternative leaving group, iodide, by treating a solution of the intermediate in a suitable solvent such as acetone, methyl ethyl ketone, and the like at about xe2x88x9210xc2x0 C. to about 50xc2x0 C. with an excess of sodium iodide or potassium iodide for about 0.25 to about 24 hours.
In many cases, the iodide is obtained in sufficiently pure form that it may be used without further purification. For ease of handling, the iodide, if not crystalline, may be lyophilized from benzene to afford an amorphous, easily handled, solid.
The activated hydroxyl group or iodide is displaced by reacting the activated intermediate with reagent Q*. In some cases, activation and displacement of the hydroxyl group may be accomplished in a single step. The activating reagent is added to a solution of the hydroxyl substituted compound in the presence of a suitable base in a suitable solvent such as dichloromethane, tetrahydrofuran, ether, DMF, benzene, acetonitrile, DMSO, and the like as described in the preceding paragraphs. The resulting activated intermediate is treated with 1-3 molar equivalents of compound Q* at a temperature of between aboutxe2x80x9478xc2x0 C. and about 50xc2x0 C. for about 15 to about 120 minutes. In some cases, it is desirable to form the activated intermediate in one solvent, isolate the activated intermediate, and conduct the displacement reaction in a different solvent. In other cases, the displacement may be conducted without isolation of the intermediate and, in cases where Q* is also used as a base, may even be concurrent with the formation of the activated intermediate.
In cases where the displacement reaction is best accomplished by using the iodide, a solution of the iodide is combined with an approximately equivalent amount (0.9-1.05 molar equivalents) of compound Q*. A silver salt of a non-nucleophilic acid, such as silver trifluoromethanesulfonate, silver tetrafluoroborate and the like is then added. Although the reaction will proceed in the absence of the silver salt, the reaction proceeds more rapidly in the presence of the silver salt. In addition, the silver salt assists in the removal of the displaced iodide from the reaction mixture which can improve the efficiency of subsequent steps. The resulting mixture is then subjected to a standard work-up procedure familiar to those skilled in the art to afford a crude product which is purified, if necessary, by recrystallization or chromatography.
An alternative method for introducing a positive charge into the side chain may be applied to side chains (i.e. R1 groups) that contain a nitrogen atom which may be quaternized by reaction with a suitable alkylating reagent AR, such as methyl iodide, methyl bromide, benzyl trichloroacetimidate, bromoacetamide, chloroacetamide, methyl trifluoromethanesulfonate, triethyloxonium tetrafluoroborate, and the like. Quaternization of the nitrogen atom in the side chain is effected by treating a solution of the compound with a slight excess (1.05 to 1.2 molar equivalents) of the alkylating reagent.
By way of example, the conversion of the hydroxyl group to a suitable leaving group can be accomplished by triflation which can be carried out in dichloromethane, dichloroethane, toluene, and the like using lutidine as a base. An aqueous citric acid work-up can be used to remove the lutidine followed by a solvent switch into a solvent such as acetonitrile. The activated hydroxyl group is displaced by reacting the activated intermediate with a reagent Q* such as DABCO acetamide to yield a protected DABCO coupled product.
The synthesis of the target compound is completed by removing any protecting groups which are present in the penultimate intermediate using standard techniques which are well known to those skilled in the art. The hydroxy protected substituent can be deprotected by reacting the hydroxy protected penultimate intermediate with an acid such HCl, H2SO4, MsOH, TFA, H3PO4, TsOH and the like or fluoride anion such as TBAF, HF-pyridine, ammonium fluoridate and the like. The carboxy protected substituent can be deprotected by hydrogenolysis (H2) in the presence of palladium on carbon, Raney Ni, Pd(OH)2/carbon, palladium on Al2O3, platinum on carbon catalyst and the like followed by reduction with a metal such as zinc and photolysis (by photolysis methods known in the art). The deprotected final product is then purified, as necessary, using standard techniques such as ion exchange chromatography, HPLC on reverse phase silica gel, MPLC on reverse phase polystyrene gel, and the like or by recrystallization.
The final product may be characterized structurally by standard techniques such as NMR, IR, MS, and UV. For ease of handling, the final product, if not crystalline, may be lyophilized from water to afford an amorphous, easily handled solid.
The compounds of the present invention are valuable intermediates for antibacterial agents, such as those described in U.S. Ser. No. 08/825,786, that are active against various Gram-positive and to a lesser extent Gram-negative bacteria, and accordingly find utility in human and veterinary medicine.
Many of the compounds that can be made in accordance with the present invention are biologically active against MRSA/MRCNS. In vitro antibacterial activity is predictive of in vivo activity when the compounds are administered to a mammal infected with a susceptible bacterial organism.